Background: Tumor necrosis factor (TNF) and Lymphotoxin alpha (LTA)are pivotal cytokines in the pathogenesis of Systemic lupus erythematosus(SLE).Objectives: to investigate the possible association of the polymorphism ofthe TNF promoter gene at position -308 and that of the LTA gene at position252 with susceptibility to SLE and with phenotypic disease features inEgyptian patients. Subjects and Methods: A case control study involving100 SLE patients and 100 unrelated healthy controls. Polymerase chainreaction and restriction fragment length polymorphism (PCR-RFLP)methods were applied to detect polymorphism in TNF Promoter (-308 G>A)& LTA 252 A>G .Results: we found that TNF-308 genotype AA wassignificantly increase by 26% in SLE patients compared to 10% in thecontrol group and genotype LTA 252 GG showed a significant increase by22% in SLE patients compared to 6% in the control group. Mutant allele Aof TNF and mutant allele G of LTA were significantly associated with SLE(p<0.001, OR=2.29, 2.31 and CI=1.49-3.52, 1.48-3.6 respectively).Genotype(AA+GA) of TNF was significantly associated with clinical manifestationsas malar rash, arthritis, oral ulcers, serositis and Systemic LupusErythematosus Disease Activity Index(SLEDAI). Genotype (GG+GA) ofLTA was significantly associated with arthritis. Conclusion: These resultssuggest that TNF and LTA genetic polymorphisms contribute to SLEsusceptibility in the Egyptian population and are associated with diseasecharacteristics.